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Prepublished online as a Blood First Edition Paper on August 14, 2003; DOI 10.1182/blood-2003-02-0478.
Submitted February 14, 2003
Accepted August 7, 2003
Induction of human  globin gene expression by histone deacetylase inhibitors
Hua Cao, George Stamatoyannopoulos*, and Manfred Jung
Division of Medical Genetics, University of Washington, Seattle, WA, USA
Department of Pharmaceutical Chemistry, Westfalische-Wilhems-Universitat, Munster, Germany
* Corresponding author; email: gstam{at}u.washington.edu.
We investigated the induction of human  globin gene activity by three classes of histone deacetylase inhibitors: amide analogues of Trichostatin A; hydroxamic acid analogues of Trapoxin; and Scriptaid and its analogues. The screening consisted of measuring the effects of these compounds on and  human gene promoter expression using cultures of GM979 cells stably transfected with a construct containing a promoter linked to firefly luciferase and a promoter linked to renilla luciferase. Compounds belonging to all three classes induced gene expression in low micromilar concentrations. Histone deacetylation studies of GM979 cells treated with HDAC inhibitors showed increased acetylation of histone H4. Compounds that increased the /+ luciferase ratio in the GM979 cells luciferase assay also increased the level of mRNA and the frequency of fetal hemoglobin containing erythroblasts in cultures of BFUe from normal adult individuals. The induction of gene expression in the luciferase assay by HDAC inhibitors was not uniform and compounds which displayed very similar degrees of inhibition of the HDAC activity in an enzymatic assay differed strikingly on their effects on gene promoter activity, raising the possibility of selectivity of HDACs interacting with the gene chromatin.
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